Vaccination had demonstrated as an alternative way to combat Helicobacter pylori challenge. In the present study, codon-optimized outer inflammatory protein gene (oipA) for Mus species codon usage, the inclusion of optimal Kozak sequence, and modified of GC content was applied to construct a novel DNA construct. The Salmonella-delivered wild type oipA construct (SL7207/poipA) and the Salmonella-delivered codon-optimized oipA construct (SL7207/poipA-opt) were prepared and their therapeutic efficacy was evaluated in H. pylori-infected mice. The codon-optimized oipA construct (poipA-opt) expressed almost six-fold higher protein than that of wild type construct (poipA) as normalized to the β-actin expression in AGS cells. Oral therapeutic immunization with SL7207/poipA-opt significantly eliminated H. pylori colonization in the stomach; and protection was related to a robust Th1/Th2 immune response. Therefore, our results suggested that fine therapeutic efficacy was related to sufficient expression of the antigen. It is supposed that codon-optimized oipA gene improves protein expression and consequently enhances the immunogenicity of DNA vaccine, which resulted in a significant reduction of bacterial loads in H. pylori infected mice. The Salmonella-delivered codon-optimized DNA construct could be a candidate vaccine against H. pylori for the clinical application.